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Combination therapy

a technology of phosphatidylinositol 3 and combination therapy, which is applied in the direction of antibody medical ingredients, drug compositions, peptides, etc., can solve problems such as refractory to treatmen

Active Publication Date: 2015-03-17
AMGEN INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]In a further embodiment, the present invention comprises the combination of (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (COMPOUND A) or a pharmaceutically acceptable salt thereof and ANTIBODY A displaying a synergistic effect.

Problems solved by technology

However, in many cases the cancers acquire resistance to these chosen therapeutic and ultimately become refractory to treatment.

Method used

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Examples

Experimental program
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Effect test

example 1

Synthesis of COMPOUND A

[0122]The synthesis of COMPOUND A is described in International Patent Application WO2010 / 029082, which is incorporated by reference in its entirety. The synthesis of this compound is described below.

(S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-{[5-(2-tert-butyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide}

[0123]

[0124]Et3N (1.54 mL, 11.1 mmol, 3 eq) is added to a solution of imidazole-1-carboxylic acid [5-(2-tert-butyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide (Step 1.1) (1.26 g, 3.7 mmol) and L-prolinamide (0.548 g, 4.8 mmol, 1.3 eq) in DMF (25 mL), under an argon atmosphere. The reaction mixture is stirred for 14 h at rt, quenched by addition of a saturated solution of NaHCO3, and extracted with EtOAc. The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 1:0→94:6), followed by trituration in Et2O to afford 1.22 g of the title compou...

example 2

Phase Ib / II Open-Label, Multi-Center Study of the Combination of Alpha-Isoform Specific PI3K Inhibitor COMPOUND A and Insulin-Like Growth Factor-1 Receptor (IGF-1R) Inhibitor ANTIBODY A in Adult Patients with Selected Advanced Solid Tumors

[0143]A multi-center, open-label, phase Ib / II study is conducted evaluating the efficacy and safety of the combination of the alpha-isoform specific PI3K inhibitor COMPOUND A and the Insulin-like growth factor-1 receptor (IGF-1R) inhibitor ANTIBODY A in adult patients with selected advanced solid tumors. First, a dose-escalation Phase Ib study is conducted to estimate the maximal terminal dose(s) (MTDs) and / or to identify the recommended Phase II dose(s) (RP2D) for the combination of the alpha-isoform specific PI3K inhibitor COMPOUND A and Insulin-like growth factor-1 receptor (IGF-1R) inhibitor ANTIBODY A in patients with PIK3CA mutated or amplified solid tumors. Second, a Phase II study is conducted to assess the antitumor activity and safety of ...

example 3

Targeting PIK3CA Mutant Breast Cancer with the Combination of Alpha-Isoform Specific PI3K Inhibitor, COMPOUND A, and IGF1-R Antibody, ANTIBODY A

[0229]The experiments below examined whether PIK3CA inhibition would also trigger IGF1-R / IRS signaling. In addition, the combination of alpha-isoform specific PI3K inhibitor, COMPOUND A, and a fully human antibody against IGF1-R, ANTIBODY A, preclinically against a PIK3CA mutant breast cancer model, MCF7, was explored. The luminal breast cancer cell line MCF7 carries an activitating PIK3CA somatic mutation. The data indicate that IGF1-R / IRS signaling is activated upon PIK3CA inhibition. COMPOUND A exhibited concentration-dependent tumor growth inhibition in vitro. ANTIBODY A alone had modest inhibitory activity. The combination of COMPOUND A and ANTIBODY A inhibited MCF7 growth synergistically in vitro (Experiment 1). This combination was further tested in an MCF7 xenograft in mice (Experiment 2). COMPOUND A monotherapy resulted in tumor sta...

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Abstract

The present invention relates to a pharmaceutical combination comprising an alpha-isoform specific phosphatidylinositol 3-kinase inhibitor compound, such as (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide), or pharmaceutically acceptable salt thereof, and an insulin-like growth factor-1 receptor (IGF1R) inhibitor (e.g., the IGF1R inhibitor ANTIBODY A, or a variant or derivative thereof), a pharmaceutical composition comprising such combination, methods for treating cancer comprising administration of therapeutically effective amounts of such inhibitors to a subject in need thereof, and uses of such combination for the treatment of cancer.

Description

RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 673,809, filed Jul. 20, 2012, and to U.S. Provisional Application Ser. No. 61 / 759,490, filed Feb. 1, 2013, which are both incorporated herein by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates to a pharmaceutical combination comprising an alpha-isoform specific phosphatidylinositol 3-kinase (PI3K) inhibitor and an insulin-like growth factor-1 receptor (IGF1R) inhibitor, a pharmaceutical composition comprising such combination, methods for treating cancer comprising administration of a therapeutically effective amount of such combination to a subject in need thereof, and uses of such combination for the treatment of cancer. Preferably, the invention relates to a pharmaceutical combination comprising the alpha-isoform specific phosphatidylinositol 3-kinase (PI3K) inhibitor compound (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/4439A61K39/395A61K39/00C07K16/28
CPCA61K31/4439A61K39/3955C07K16/2863A61K2039/505C07K2317/565C07K2316/96A61K2300/00A61P15/00A61P35/00A61P35/02A61P35/04A61P43/00C07K2317/73C07K2317/76A61K31/427
Inventor HUANG, XIZHONGPETERS, MALTESCHUMACHER, KARL MARIACAO, ZHU ALEXANDERGANSERT, JENNIFER LORRAINECHANG, DAVID DONG EUN
Owner AMGEN INC
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